Reversing the loss of brain connections in Alzheimer’s disease

June 21, 2013

The first experimental drug to boost brain synapses lost in Alzheimer’s disease has been developed by researchers at Sanford-Burnham.

The drug, called NitroMemantine, combines two FDA-approved medicines to stop the destructive cascade of changes in the brain that destroys the connections between neurons, leading to memory loss and cognitive decline.

The decade-long study, led by Stuart A. Lipton, M.D., Ph.D., professor and director of the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, who is also a practicing clinical neurologist, shows that NitroMemantine can restore synapses (connections between nerve cells) that have been lost during the progression of Alzheimer’s in the brain.

The focus on a downstream target to treat Alzheimer’s, rather than on amyloid beta plaques and neurofibrillary tangles—approaches which have shown little success—“is very exciting because everyone is now looking for an earlier treatment of the disease,” Lipton said.

“These findings actually mean that you might be able to intercede not only early but also a bit later.” And that means that an Alzheimer’s patient may be able to have synaptic connections restored even with plaques and tangles already in his or her brain.

Targeting lost synapses

In their study, conducted in animal models as well as brain cells derived from human stem cells, Lipton and his team mapped the pathway that leads to synaptic damage in Alzheimer’s. They found that amyloid beta peptides, which were once thought to injure synapses directly, actually induce the release of excessive amounts of the neurotransmitter glutamate from brain cells called astrocytes that are located adjacent to the nerve cells.

Normal levels of glutamate promote memory and learning, but excessive levels are harmful. In patients suffering from Alzheimer’s disease, excessive glutamate activates extrasynaptic receptors, designated eNMDA receptors (NMDA stands for N-methyl-D-aspartate), which get hyperactivated and in turn lead to synaptic loss.

How NitroMemantine works

Lipton’s lab had previously discovered how a drug called memantine can be targeted to eNMDA receptors to slow the hyperactivity seen in Alzheimer’s. This patented work contributed to the FDA approval of memantine in 2003 for the treatment of moderate to severe Alzheimer’s disease. However, memantine’s effectiveness has been limited. The reason, the researchers found, was that memantine—a positively charged molecule—is repelled by a similar charge inside diseased neurons; therefore, memantine gets repelled from its intended eNMDA receptor target on the neuronal surface.

In their study, the researchers found that a fragment of the molecule nitroglycerin—a second FDA-approved drug commonly used to treat episodes of chest pain or angina in people with coronary heart disease—could bind to another site that the Lipton group discovered on NMDA receptors. The new drug represents a novel synthesis connecting this fragment of nitroglycerin to memantine, thus representing two FDA-approved drugs connected together.

Because memantine rather selectively binds to eNMDA receptors, it also functions to target nitroglycerin to the receptor. Therefore, by combining the two, Lipton’s lab created a new, dual-function drug. The researchers developed 37 derivatives of the combined drug before they found one that worked, Lipton said.

By shutting down hyperactive eNMDA receptors on diseased neurons, NitroMemantine restores synapses between those neurons. “We show in this paper that memantine’s ability to protect synapses is limited,” Lipton said, “but NitroMemantine brings the number of synapses all the way back to normal within a few months of treatment in mouse models of Alzheimer’s disease. In fact, the new drug really starts to work within hours.”

To date, therapies that attack amyloid plaques and neurofibrillary tangles have failed. “It’s quite disappointing because I see really sick patients with dementia. However, I’m now optimistic that NitroMemantine will be effective as we advance to human trials, bringing new hope to both early and later-stage Alzheimer’s patients,” Lipton said.

Comments (9)

I am not a bio or medical scientist, but a behavioural scientist. I understand that keep learning new things at advanced age is a best way of preventing loss or building up new synapses, to avoid or slow down Alzheimer even in worst cases. My impression is that in case of Alzheimer, this psychological approach is better than any medical treatment. What is the opinion of various experts?

I agree with Jennifer, very timely developments – I am just very sad that we are still going to lose many seniors to this before the product can be successfully brought to market. That is, brought to market without rip off pricing and hopefully that this was all done with proper testing/vetting and no shortcuts.

This looks so very promising but we’re gonna have to hold our breath and wait for it to pan out. Because me for one, I will be all over this bad boy down the road if works – I plan to live a very, very long productive life but not if it’ll mean suffering from the disease and having my loved ones suffer along with me.

What I wonder is if they get this working for patients with disease and it can help them get back to normal… .can it also get them back to above normal if they keep using them? for patients without any massive disease/damage in the first place can it make them above normal? Most adults have had a few minor concussions in their lifetime just from playing normal sports, or drank enough red wine to lost some brain cells… or who knows what to not be as sharp as we once were (senior moment joke goes here). I know that most of these drugs/cures/advancements are created to fix problems, but I have to wonder at some point (soon) if we can’t use this same effort to go above normal for the brain. (please get back to mining the spice http://dune.wikia.com/wiki/Spice_mining). Seems like there is often so much positive attention for solving diseases, but the opposite opinion that Nootropics can boost normal people to superhero like results often seems shunned or at least in the crazy med students cramming for exams, huddled together in redbull fueled hives of self indulgent steroid like crazed shortcut masters.

What if Ray’s predictions of the singularity or us merging with machines did not quite factor in the What if components of super effective Nootropics that could radically change things in several unexpected ways…. ??

I wanted to plug the http://www.23andme.com website as I think it is important for people to check their own dna for possible risk factors for diseases like Alzheimers, etc. I personally did this at 23andme website for the cost of $99 (you spit in a tube that they mail you and …presto, you get some really cool and amazing info back in just a mater of weeks) ,then I do also pay $9/month to be active on the forums and get updated results, etc. I was found to have a 14.4% increased chance of Alzheimer’s, as an AP04E gene holder myself…(even though I have no family history and other factors point away from this… maybe the way to see this is I am 85.6% unlikely to get Alzheimers…. (so I improve my fish oils, coconut oil, exercise, brain games, and a dozen other things to get ahead of the disease, even though common research hints there is not much you can do).

Here is one of the focused forums on the subject where others (like me) that have the AP0E gene can crowd source all the latest research articles and share what they are doing and also sign up for advanced trials, brain scans, etc.. all amazing things that are advancing the chance for a cure, or treatments, or other. https://www.23andme.com/you/community/thread/20469/

This is an encouraging development. It’s not entirely the case that treatments targeting plaques have been unsuccessful, though. There is a large Phase III clinical trial of a drug called Rember, based on methylene blue, that emerged from successful animal studies (and anecdotal reports suggest that existing formulations of methylene blue, which is a well known drug with a long history, can reverse dementia in Alzheimer’s patients as well). With the US population confronting age-related dementias in greater numbers, these are both timely developments.

I’ve heard great anecdotal things about coconut oil too, but the likelihood of a large cohort study based on coconut oil is unlikely (because it’s cheap and readily available, so it can’t be patented by pharma). :(

The CDC and various Universities and Foundations do fund research on orphan drugs like that, but the problem of course is that there are so many of them and the non-profits only have so much money …. Perhaps eventually we’ll get around to studies on such drugs and supplements, it just might take a while.